Candida species, the third most common cause of healthcare-associated bloodstream infections, causes approximately 60,000 cases of hematogenously disseminated candidiasis per year in the United States, resulting in billions of dollars of healthcare expenditures. Despite current antifungal therapy, mortality remains unacceptably high. Because of the rising incidence of life-threatening candidiasis and high treatment failure rates, more effective prophylactic and therapeutic strategies are needed.
The primary host defense mechanism against disseminated candidiasis is phagocytic killing of the organism. Only phagocytic cells are capable of directly killing Candida in vitro. Additionally, within thirty-minutes of intravenous inoculation of Candida in mice, rabbits, dogs, or humans, yeasts are retained within the reticuloendothelial system, especially in the liver. The liver, rich in Kupffer macrophages, is capable of clearing 99.9% of yeast in the portal system during a single pass, underscoring the effectiveness of phagocytic defense mechanisms against the fungus. Hence, resistance of C. albicans to phagocyte killing is an important virulence function of the organism.
Cell surface glycosyl phosphatidylinositol (GPI)-anchored proteins are at the critical interface between pathogen and host, making these proteins likely participants in host-pathogen interactions.
The identification of effectors in the regulatory pathways of the organism that contribute to virulence offers the opportunity for therapeutic intervention with methods or compositions that are superior to existing antifungal agents. The identification of cell surface proteins or hyphal proteins that affect a regulatory pathway involved in virulence is particularly promising because characterization of the protein enables immunotherapeutic techniques that are likely superior to or synergistic with existing antifungal agents when fighting a candidal infection.
The virulence of C. albicans is regulated by several putative virulence factors of which adherence to host constituents and the ability to transform from yeast-to-hyphae are among the most critical in determining pathogenicity. While potent antifungal agents exist that are microbicidal for Candida, the attributable mortality of candidemia is approximately 38%, even with treatment with potent anti-fungal agents such as amphotericin B. Also, existing agents such as amphotericin B tend to exhibit undesirable toxicity. Although additional antifungals may be developed that are less toxic than amphotericin B, it is unlikely that agents will be developed that are more potent. Therefore, either passive or active immunotherapy to treat or prevent disseminated candidiasis is a promising alternative to standard antifungal therapy.
Lethal infections of antibiotic resistant pathogenic bacteria, like infections resulting from Candida, are becoming increasingly frequent. Moreover, the risk of contracting these lethal infections is extremely high for many at-risk patients in intensive care units (ICUs) every year as well as for soldiers deployed to front line combat zones. Acinetobacter species are a frequent source of infection in hospitalized patients and soldiers, in particular the species Acinetobacter baumannii. Acinetobacter is a genus of gram negative bacteria belonging to the Gammaproteobacteria. Acinetobacter species contribute to the mineralization of aromatic compounds in the soil. Unfortunately, no technology presently exists that prevents Acinetobacter infections, aside from standard hand washing and other infection control practices in hospital settings.
Active and passive immunization of individuals against antibiotic resistant pathogenic bacteria presents a convenient and potentially cost effective method of trying to combat these infections. However, identifying and developing effective antigenic targets for implementation of passive and active immunizations against bacteria in general presents a difficult challenge because of the vast array of bacterial species. The identification of compounds that affect the virulence of specific bacterial families or genera provides an opportunity to develop novel therapeutic interventions. In particular, the recognition of ubiquitous cell surface proteins that are present on the bacterial families or genera that can be identified by an individual's immune system will enable immunotherapeutic techniques. These techniques will likely be superior to and also can act in synergy with antibiotics to prevent or treat bacterial infections.
There accordingly exists a need for compounds and methods that reduce the risk of infectious diseases related to Candida and bacterial infections and provide effective therapies. The present invention satisfies this need and provides related advantages as well.